2-233682324-T-G

Variant names:

• chr2-233682324-T-G
• rs17868323
• NM_019077.3:c.387T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019077.3(UGT1A7):​c.387T>G​(p.Asn129Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,612,848 control chromosomes in the GnomAD database, including 314,252 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N129R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.61 (28597 hom., cov: 32)
  • Exomes 𝑓: 0.62 (285655 hom.)
• Consequence: UGT1A7 NM_019077.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -13.7

Genes affected

UGT1A7 (HGNC:12539): (UDP glucuronosyltransferase family 1 member A7) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has moderate glucuronidase activity with phenols. [provided by RefSeq, Jul 2008]

UGT1A10 (HGNC:12531): (UDP glucuronosyltransferase family 1 member A10) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity on mycophenolic acid, coumarins, and quinolines. [provided by RefSeq, Jul 2008]

UGT1A8 (HGNC:12540): (UDP glucuronosyltransferase family 1 member A8) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene has glucuronidase activity with many substrates including coumarins, phenols, anthraquinones, flavones, and some opioids. [provided by RefSeq, Jul 2008]

UGT1A9 (HGNC:12541): (UDP glucuronosyltransferase family 1 member A9) This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, such as steroids, bilirubin, hormones, and drugs, into water-soluble, excretable metabolites. This gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter. The enzyme encoded by this gene is active on phenols. [provided by RefSeq, Jul 2008]

UGT1A (HGNC:12529):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.1985556E-6).
• BP6: Variant 2-233682324-T-G is Benign according to our data. Variant chr2-233682324-T-G is described in ClinVar as [Benign]. Clinvar id is 440386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UGT1A7	NM_019077.3	c.387T>G	p.Asn129Lys	missense_variant	Exon 1 of 5	ENST00000373426.4	NP_061950.2
UGT1A10	NM_019075.4	c.855+44947T>G		intron_variant	Intron 1 of 4	ENST00000344644.10	NP_061948.1
UGT1A8	NM_019076.5	c.855+63762T>G		intron_variant	Intron 1 of 4	ENST00000373450.5	NP_061949.3
UGT1A9	NM_021027.3	c.855+9535T>G		intron_variant	Intron 1 of 4	ENST00000354728.5	NP_066307.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UGT1A7	ENST00000373426.4	c.387T>G	p.Asn129Lys	missense_variant	Exon 1 of 5	1	NM_019077.3	ENSP00000362525.3
UGT1A10	ENST00000344644.10	c.855+44947T>G		intron_variant	Intron 1 of 4	1	NM_019075.4	ENSP00000343838.5
UGT1A9	ENST00000354728.5	c.855+9535T>G		intron_variant	Intron 1 of 4	1	NM_021027.3	ENSP00000346768.4
UGT1A8	ENST00000373450.5	c.855+63762T>G		intron_variant	Intron 1 of 4	1	NM_019076.5	ENSP00000362549.4

Frequencies

GnomAD3 genomes AF: 0.613 AC: 92597 AN: 151158 Hom.: 28571 Cov.: 32

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.586

GnomAD2 exomes AF: 0.588 AC: 142291 AN: 242112 AF XY: 0.595

Gnomad AFR exome AF: 0.621

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.423

Gnomad FIN exome AF: 0.691

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.622 AC: 909731 AN: 1461574 Hom.: 285655 Cov.: 101 AF XY: 0.624 AC XY: 453364 AN XY: 727060

African (AFR) AF: 0.625 AC: 20929 AN: 33472

American (AMR) AF: 0.439 AC: 19608 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 15003 AN: 26130

East Asian (EAS) AF: 0.401 AC: 15910 AN: 39680

South Asian (SAS) AF: 0.649 AC: 55967 AN: 86246

European-Finnish (FIN) AF: 0.690 AC: 36840 AN: 53400

Middle Eastern (MID) AF: 0.587 AC: 3383 AN: 5764

European-Non Finnish (NFE) AF: 0.634 AC: 705195 AN: 1111828

Other (OTH) AF: 0.611 AC: 36896 AN: 60378

GnomAD4 genome AF: 0.613 AC: 92673 AN: 151274 Hom.: 28597 Cov.: 32 AF XY: 0.612 AC XY: 45234 AN XY: 73874

African (AFR) AF: 0.624 AC: 25744 AN: 41270

American (AMR) AF: 0.514 AC: 7821 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1980 AN: 3458

East Asian (EAS) AF: 0.423 AC: 2171 AN: 5128

South Asian (SAS) AF: 0.652 AC: 3132 AN: 4802

European-Finnish (FIN) AF: 0.699 AC: 7332 AN: 10490

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42508 AN: 67616

Other (OTH) AF: 0.587 AC: 1234 AN: 2102

Alfa AF: 0.608 Hom.: 37369

Bravo AF: 0.596

TwinsUK AF: 0.619 AC: 2295

ALSPAC AF: 0.649 AC: 2503

ExAC AF: 0.589 AC: 71531

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12172214, 12122597, 11677206, 11037804) -

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0080
DANN	Benign	0.51
DEOGEN2	Benign	0.15	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.035	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.19	N
PhyloP100		-14
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.011
Sift	Benign	0.30	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.018
MutPred		0.15		Gain of methylation at N129 (P = 0.0381);
MPC		0.12
ClinPred		0.032	T
GERP RS		-9.0
PromoterAI		0.012	Neutral
Varity_R		0.096
gMVP		0.21
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs17868323; hg19: chr2-234590970; COSMIC: COSV60830578; COSMIC: COSV60830578;